PROJECT SUMMARY ? PROJECT 3 The three major risk factors for Alzheimer's disease are age, female gender and ApoE4 genotype. AD can be divided into two groups by age at onset: early onset (onset < 65 years; EOAD) and late onset (onset > 65 years; LOAD). Human ApoE has three major isoforms: E2, E3, and E4. APOE4 is the strongest and most highly replicated genetic risk factor for late-onset AD (LOAD). One and two copies of APOE4 increase by a 3.7- and 12-fold AD risk and decrease the age of onset by 8 to 15 years relative to APOE3/3 carriers. Findings from the first four years of our program project indicate that the perimenopause transition leads to a bioenergetic crisis in rat brain which activates a cascade of adaptive responses associated with an Alzheimer's-like phenotype. To advance both mechanistic understanding and clinical translation, we focus the renewal of our program project on the hypothesis that ApoE4 positive females experience a triple hit: 1) ApoE4 genotype; 2) Aging and 3) Perimenopause. We propose that it is the perimenopausal bioenergetic shift in brain that creates greater risk of AD in women with a single copy of the APOE4 gene. The objective of this study is to 1) determine whether the perimenopausal transition in women is a transition state of risk for prodromal AD and 2) whether the ApoE4 genotype is a modifier that accelerates clinical indicators of risk of Alzheimer's disease that emerge during the perimenopause. Outcomes of these analyses will provide evidence regarding early stage development of three indicators of Alzheimer's risk, hypometabolism, brain atrophy and beta amyloid deposition. We have developed 3 approaches to test this hypothesis: a) a prospective molecular and neuroimaging study of 150 women; b) determination of the effect of the APOE4 genotype in 600 postmenopausal women on cognitive decline from the USC Atherosclerosis Research Unit, the Elite Trial; c) determination of the effect of the APOE4 genotype and menopause on the lifespan trajectories of approximately 5,000 women derived from 10,000 MRI derived brain volume metrics and clinical data available through the ENIGMA working groups. We will also analyze 33,195 subjects (men and women from ENIGMA) with MRIs and genomes for the effect of sex (males vs females), ApoE4 genotype using a meta-regression model. We hypothesize that females and ApoE (e2/e3/e4 allele) risk loading will also demonstrate accelerated hypometabolic phenotype and an earlier decrease in hippocampal volumes. This project is truly a multi- disciplinary effort bringing together a strong investigative team. Drs. Roberta Brinton (USC Schools of Pharmacy and Medicine), Meng Law (USC School of Medicine-Neuroradiology), Paul Thompson and Arthur Toga (USC School of Medicine-Institute of Neuroimaging and Informatics with the Laboratory of Neuro Imaging (LONI), Howard Hodis (USC School of Medicine), Wendy Mack (USC School of Medicine). Our collaborator Dr. Lisa Mosconi (New York University School of Medicine, NYU) has expertise in conducting brain imaging studies of subjects at risk for AD, including young to late-middle aged persons.